Gene Expression of Proresolving Lipid Mediator Pathways Is Associated With Clinical Outcomes in Trauma Patients.
Gene Expression of Proresolving Lipid Mediator Pathways Is Associated With Clinical Outcomes in Trauma Patients.
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DOI：
10.1097/ccm.0000000000001312
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发表时间：
2015-12
影响因子：
8.8
通讯作者：
Irimia D
中科院分区：
文献类型：
--
作者：
Orr SK;Butler KL;Hayden D;Tompkins RG;Serhan CN;Irimia D
专门的促脂介质已经成为炎症的强大调节剂和溶解的激活剂。动物模型显示专门的促脂质介质对严重烧伤后的生存和伤口愈合有显著的益处。迄今为止，还没有研究调查专门的促脂质介质及其与创伤后人类其他脂质介质途径的关系。在这里，我们确定创伤后预后不良的患者是否有调节失调的脂质介质通路。我们研究了18个基因的血液白细胞表达，这些基因对专门的促炎性脂质介质和促炎性脂质介质的合成、信号传导和代谢至关重要，并将这些表达模式与炎症和宿主对损伤的反应研究中创伤患者的临床结果联系起来。七个美国医疗创伤中心。96名患者参加了炎症和宿主对损伤的反应研究，这些患者在钝性创伤后明确分为简单和复杂的恢复。28名健康志愿者作为对照。没有。在每个患者中，18个感兴趣的基因被用来计算不同脂质介质家族的评分，包括溶解蛋白、脂毒素、前列腺素和白三烯，以及白三烯与溶解蛋白的评分比率。采用简单的加权方案建立评分，同时考虑了负责脂质介质生物合成和功能的酶和受体的依赖和独立活性。ALOX12、PTGS2、PTGES、PTGDS、ALOX5AP、LTA4H、FPR2、PTGER2、LTB4R、HPGD、PTGR1、CYP4F3在创伤后28天内的表达差异有统计学意义（p < 0.05）。当所有基因组合成评分时，无并发症恢复的患者具有差异和较高的resolvin评分（p < 0.001）和较低的白三烯评分（p < 0.001）。计算每位患者的最终合并比率，创伤后白三烯评分与溶解评分比率在无复杂临床病程的患者中显著降低（p < 0.001）。单纯康复的创伤患者溶解蛋白通路基因表达较高，白三烯溶解蛋白通路基因表达比较低。通过更复杂的模型进一步验证这些发现，包括专门的促进脂质介质脂组学和/或蛋白质表达的测量，以及确定相关的治疗靶点，可能会影响创伤患者的临床管理。
Specialized proresolving lipid mediators have emerged as powerful modulators of inflammation and activators of resolution. Animal models show significant benefits of specialized proresolving lipid mediators on survival and wound healing after major burn trauma. To date, no studies have investigated specialized proresolving lipid mediators and their relation to other lipid mediator pathways in humans after trauma. Here we determine if patients with poor outcomes after trauma have dysregulated lipid mediator pathways. We studied blood leukocyte expression of 18 genes critical to the synthesis, signaling, and metabolism of specialized proresolving lipid mediators and proinflammatory lipid mediators, and we correlated these expression patterns with clinical outcomes in trauma patients from the Inflammation and the Host Response to Injury study. Seven U.S. medical trauma centers. Ninety-six patients enrolled in the Inflammation and Host Response to Injury study, after blunt trauma and unambiguously classified as having uncomplicated or complicated recoveries. Twenty-eight healthy volunteers were enrolled as controls. None. Within each patient, the 18 genes of interest were used to calculate scores for distinct families of lipid mediators, including resolvins, lipoxins, prostaglandins, and leukotrienes, as well as leukotriene to resolvin score ratios. Scores were built using a simple weighting scheme, taking into consideration both dependent and independent activities of enzymes and receptors responsible for lipid mediator biosynthesis and function. Individually, ALOX12, PTGS2, PTGES, PTGDS, ALOX5AP, LTA4H, FPR2, PTGER2, LTB4R, HPGD, PTGR1, and CYP4F3 were expressed differentially over 28 days posttrauma between patients with uncomplicated and complicated recoveries (p < 0.05). When all genes were combined into scores, patients with uncomplicated recoveries had differential and higher resolvin scores (p < 0.001) and lower leukotriene scores (p < 0.001). A final combined ratio was calculated for each patient, and posttrauma leukotriene score to resolvin score ratios were significantly lower in patients with uncomplicated clinical courses (p < 0.001). Trauma patients with uncomplicated recoveries had higher resolvin pathway gene expression and lower gene expression ratios of leukotriene:resolvin pathways. Further validation of these findings with more complex modeling including measures with specialized proresolving lipid mediator lipidomics and/or protein expression, and identifying associated therapeutic targets, may influence the clinical management of trauma patients.